Terrence C. Dahl

Degradation kinetics of oxycarbonyloxymethyl prodrugs of phosphonates in solution.

Phosphonate analogs of nucleotides have recently received considerable attention as potential antiviral agents. The ionic character of these agents limits their permeability across the human intestinal mucosa, resulting in low bioavailability after oral administration (1,2). We have previously demonstrated the utility of the bis-isopropyloxycarbonylmethyl (bis-POC) moiety in improving the oral bioavailability of phosphonate nucleotides (3–5). The bis-POC promoiety utilizes the oxycarbonyloxymethyl spacer group. The lipophilicity of the prodrug can be adjusted by varying the chain length of the alcohol. Scheme I depicts the putative enzymatic steps involved in the bioconversion of bis-POC prodrugs of a phosphonate moiety to the corresponding phosphonate monoester. The initial enzymatic catalysis is believed to occur at the site remote from phosphorus, thus avoiding enzymatic phosphorylation. The oxycarbonyloxymethyl promoiety has been previously applied to amines and hindered alcohols (6,7). Safadi and co-workers utilized this spacer group promoiety to enhance the water solubility of various compounds by chemically linking inorganic phosphates to hindered alcohols and amines (6). These prodrugs were chemically unstable and were not suitable as commercially viable pharmaceuticals. Alexander and co-workers also applied this spacer group to alter the lipophilicity of amine containing agents (7). To our knowledge, the degradation kinetics and hydrolytic pathway of oxycarbonyloxymethyl spacer group applied to phosphonates have not been reported. In the present study, we have applied the bis-POC promoiety to 9-((R)-2-(phosphonomethoxy)ethyl)adenine (Adefovir, PMEA) and to 9-((R)-2-(phosphonomethoxy)propyl) adenine (Tenofovir, PMPA). The chemical stability of bisPOC PMEA and bis-POC PMPA (Scheme II) in solution were investigated. In addition, the O incorporation studies were conducted to elucidate the degradation pathway(s) for the hydrolysis of the prodrug in aqueous solution. MATERIALS AND METHODS

Effect of Carbonate Salts on the Kinetics of Acid-Catalyzed Dimerization of Adefovir Dipivoxil

AbstractPurpose. The chemical stability and product(s) distribution of adefovir dipivoxil (ADV) was examined in the presence of soluble and insoluble carbonate salts. Methods. Chemical stability of ADV in the solid state at 60°C/30% RH was examined. Stability was also examined in the presence of excess formaldehyde vapor at 23°C/53% RH. ADV and its degradation product(s) were determined by reverse phase HPLC. Results. Addition of aqueous soluble carbonate salts, such as sodium carbonate, compromised the stability of ADV in solid state. However, aqueous insoluble carbonates, such as calcium carbonate and magnesium carbonate, enhanced the stability of ADV as compared to the control formulation. Pivalic acid, a degradation product of ADV, was shown to accelerate the degradation rate of ADV in solid state. The de-stabilizing effect of this acid on ADV stability was diminished in the presence of magnesium carbonate. Pivalic acid also increased the rate at which ADV dimers were formed in the presence of formaldehyde vapor. Addition of insoluble carbonates reduced the rate of formaldehyde-catalyzed dimerization of ADV. Conclusions. Addition of insoluble carbonate salts decreased the rate of degradation of ADV by minimizing the extent of formaldehyde-catalyzed dimerization in solid state.

Biexponential decomposition of a neuraminidase inhibitor prodrug (GS-4104) in aqueous solution

AbstractPurpose. To examine the degradation kinetics and identify the degradation products of a neuraminidase inhibitor prodrug, GS-4104. Methods. Degradation was studied as a function of pH and temperature using a stability-indicating RP-HPLC assay. Degradation products were isolated by RP-HPLC and identified by NMR. Specific rate constants were calculated based on a scheme defined by product(s) analysis. Results. Three distinct degradation products were observed in the pH region studied (pH 2−8): isomer I, GS-4071, and isomer II. Isomer I resulted from the N, N-migration of the acetyl group. GS-4071 was formed by the hydrolysis of the ethyl ester. Both GS-4071 and isomer I degraded further to isomer II by N, N-acyl migration and ester hydrolysis, respectively. The N, N-acyl migration reaction was characterized using two dimensional heteronuclear multiple bond correlation (HMBC) NMR. The decomposition kinetics of GS-4104 follow a biexponential decay at pH 2−7. The degradation kinetics of GS-4104 at pH 4.0, 70°C were independent of the initial GS-4104 concentration. Conclusions. The degradation profile indicates that development of solution or solid dosage form of GS-4104 with adequate shelf-life stability at room temperature is feasible.